Capillary Precipitation of a Highly Polymorphic Organic Compound

Abstract

Crystallization of pharmaceutically active compounds from saturated solutions by means of solvent evaporation typically involves a nucleation and growth process. At slow solvent evaporation rates, nuclei of the stable forms (polymorphs) will grow at the expense of any metastable forms present in the crystallizing mixture. A relatively phase-pure product is thus produced. However, if nucleation can be suppressed such that sufficiently high supersaturation ratios are obtained, then even nuclei of the metastable forms will grow rapidly and may persist in the end product. This work details the investigation of the crystallization of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY, a synthetic drug−substance intermediate) from supersaturated ethanol solutions. Nucleation was suppressed by crystallizing from small liquid volumes in glass-capillary tubes. It was found that the resultant crystals displayed a range of metastable forms. Results are discussed relative to classic nucleation theory.

Characterization and Selective Crystallization of Famotidine Polymorphs

“…6 The traditional methods, such as varying solvent, 7 temperature, 8 supersaturation, 9 cooling rate, 10 and seeding strategy, 11,12 have been extensively applied to control the polymorphic behavior of a compound during its crystallization process. 13 Recent approaches for discovery and selection of polymorphic forms of a compound include crystallization with tailor-made soluble additives, [14][15][16][17] polymer heteronuclei, 18,19 crystallization on various substrates and templates, [20][21][22] laser induced nucleation, 23 solventdrop grinding, 24 spray drying, 25 supercritical fluid crystallization, 26 capillary crystallization, 27,28 crystallization confined in nanopores, 29 etc. In spite of above great efforts the fundamental mechanisms and molecular properties that drive crystal form diversity, specifically the nucleation of polymorphic forms, are not well understood.…”

Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals

“…Application of the technique to the highly polymorphic compound 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) resulted in measured supersaturation levels as high as 60 and clearly showed a correlation between the supersaturation level attained and the polymorph produced. 26 Capillary crystallization of nabumetone solutions produced a new polymorphic form whose appearance was independent of the identity of the solvent. 27 It can also be shown theoretically that as supersaturation increases, the rate of nucleation of metastable forms becomes competitive with the rate of nucleation of stable forms.…”

Concomitant Polymorphism in Confined Environment

“…It is well known that nucleation becomes more difficult as the container volume decreases. Our approach has been the manipulation of the rate of solvent evaporation on pico-and nano-liter droplets while providing the nucleation templating effect of the SAM_s The rate of evaporation impacts the level of supersaturation generated with high supersaturation favoring the formation of high energy metastable polymorphic forms while with low supersaturations, the thermodynamically stable form typically nucleates Capillary crystallization employs a different strategy where slow solvent evaporation in constrained environments (capillaries) decreases the probability of nucleation since the volume is small and clean with no templating surface, thus allowing high supersaturations and metastable forms (39). Crystallization confined in nanopores is an example where polymorph selectivity can be directed by suppressing the nucleation of unwanted polymorphs whose critical nucleus size are larger than the pore dimensions.…”